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Neuroradiology |
1 From the Section of Diagnostic Radiology, Department of Clinical Physiopathology (M. Mascalchi, C.T., N.V.) and Section of Neurophysiopathology (F.L.), University of Florence, Viale Morgagni 85, 50134 Florence, Italy; Department of Radiology, University of Pisa, Italy (M.C.); Department of Clinical Neurology, Ospedale Bellaria, University of Bologna, Italy (F.S., R.P., C.A.T.); Department of Neurophysiopathology, Ospedale di Empoli, Italy (M. Macucci); IRCSS Stella Maris, Calambrone, Pisa, Italy (M.T.); and Institute of Genetic Medicine, University of Ferrara, Italy (A.F.). Received April 4, 2001; revision requested May 14; revision received July 23; accepted November 20. Supported by grant No. E444 from Telethon-Italy. Address correspondence to M. Mascalchi.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Brain MR imaging and single-voxel proton MR spectroscopy of the right cerebellar hemisphere and pons were performed in 30 patients with sporadic (n = 16) or inherited (n = 14) degenerative ataxia and in 20 healthy control subjects. Several indexes of brainstem and cerebellar atrophy were measured on MR images, as well as the N-acetylaspartate/creatine (NAA/Cr), choline/Cr (Cho/Cr), and myo-inositol/Cr (mI/Cr) ratios in the MR spectra. Differences between patients and subjects were evaluated with the Kruskal-Wallis and Mann-Whitney tests, whereas correlation of clinical, MR imaging, and spectroscopic data was assessed with nonparametric Spearman rank correlation.
RESULTS: Measurements of brainstem and cerebellar atrophy obtained from MR images revealed patients had olivopontocerebellar atrophy (OPCA) (n = 11), spinal atrophy (SA) (n = 8), or corticocerebellar atrophy (CCA) (n = 4). Seven patients did not fulfill the criteria for any group and were considered undefined. In patients with OPCA, the pontine and cerebellar NAA/Cr and Cho/Cr ratios were significantly decreased when compared with those of the control subjects. Pontine and cerebellar NAA/Cr ratios were also significantly reduced in patients with SA and CCA. Five patients with undefined ataxia had a substantial decrease of pontine or cerebellar NAA/Cr ratio when compared with that of the control subjects. In patients with OPCA, the pontine NAA/Cr ratio (but not the atrophy measurements) showed a correlation (P = .04) with disability.
CONCLUSION: MR spectroscopy is a useful complement to MR imaging in patients with degenerative ataxia.
© RSNA, 2002
Index terms: Brain, atrophy, 151.1839, 153.1839 • Brainstem, abnormalities, 158.1839 • Brainstem, MR, 158.12145 • Magnetic resonance (MR), spectroscopy, 158.12145 • Spinal cord, diseases, 341.189
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Proton MR spectroscopy allows noninvasive in vivo biochemical analysis of small volumes of interest (eg, a single voxel) within the brain parenchyma (7). Preliminary studies in a few patients (8–12) revealed decreased concentrations of the neuronal marker N-acetylaspartate (NAA) and the NAA/creatine (NAA/Cr) ratio in the cerebellum and pons of patients with degenerative ataxia. The purpose of our study was to investigate whether proton MR spectroscopy is a useful complement to MR imaging in patients with degenerative ataxia.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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In each patient, disability was assessed by a neurologist (M. Mascalchi) at the time of MR examination by means of a simple interview and a standard neurologic examination. Disability assessment allowed classification of each patient into one of four categories of increasing disability (5): 1 = mild ataxia, able to work (n = 12); 2 = unable to work, able to walk and perform activities of daily living (n = 10); 3 = same as 2, but unable to walk unassisted or chairbound (n = 6); and 4 = chairbound, dependent on others for activities of daily living (n = 2).
Twenty healthy control subjects were studied by using the same MR spectroscopic protocol. They were recruited among personnel working in the MR imaging unit (ie, physicians, physicists, students, nurses, and their parents). They had no personal or familial history of neurologic diseases and received normal neurologic examination results. Fifteen of them also underwent MR imaging, which provided reference values for the morphometric evaluation detailed below.
MR Imaging Protocol
MR imaging included sagittal T1-weighted spin-echo 500/15 (repetition time msec/echo time msec) imaging and transverse intermediate-weighted 2,400/30 spin-echo and T2-weighted spin-echo 2,400/100 imaging. Section thickness was 5 mm, field of view was 240 x 240 mm, and matrix size was 256 x 256.
After imaging, single-voxel MR spectroscopy was performed by using the PROBE/SV system (GE Medical Systems), which provides automated global and local shimming and chemical shift selective water suppression (18). Voxels of 1.5 x 1.5 x 1.5 cm (3.4 cm3) were acquired in the deep right cerebellar hemisphere (encompassing the dentate nucleus) in 29 patients and 18 subjects and in the basis pontis in 28 patients and 20 subjects. Three patients and two subjects requested to end the examination because of claustrophobia. Although we tried to avoid inclusion of cerebrospinal fluid spaces in the volume of interest, some contamination of the voxel with fluid was unavoidable in some patients with severe brainstem or cerebellar atrophy.
A short echo time–stimulated echo acquisition mode, or STEAM sequence (19), was used. Acquisition parameters were 2,020/30 with a 13.7-msec mixing time, and 256 signal averages were collected. All spectra were acquired with a bandwidth of 2,500 Hz, which corresponded to 2,048 points, and acquisition of a single voxel took 9.58 minutes. Data were analyzed with the Spectral Analysis General Electric/Interactive Data Language program (SAGE/IDL; GE Medical Systems) on an Ultra workstation (Sun Microsystems, Palo Alto, Calif). After spectral offset referencing to the water peak, data processing involved the following steps: apodization of corrected time-domain signal by multiplying a gaussian line broadening of 3 Hz to enhance the signal-to-noise ratio, zero filling, high-pass convolution filtering with 20-Hz bandwidth, fast Fourier transform, and zero- and first-order phase correction. No baseline manipulation was performed.
Data Analysis
MR imaging.—By using the surface and linear measurement techniques proposed by Wullner et al (4), the sizes of the brainstem, cerebellum, and cervical spinal cord were determined in patients and subjects by using a manual tracing device on an independent console (SPARCstation; Sun Microsystems). The sizes were obtained by an operator (C.T.) who was blind to the group to which the individual belonged (ie, patient or control group) and to the MR spectroscopic and clinical data. Measurements included areas of the basis pontis, the fourth ventricle, and the cerebellar vermis in midsagittal T1-weighted images. The area of the cerebellar hemisphere located next to the middle cerebellar peduncle was measured on the first parasagittal T1-weighted image. The thickness of the middle cerebellar peduncles, the area of the medulla on the horizontal plane at the level of the inferior olivary complex, and the area of the cervical spinal cord on the horizontal plane at the level of the dens axis were measured on transverse T2-weighted images. All measurements were normalized to the area of the posterior cranial fossa (PCF) on midsagittal T1-weighted images.
To evaluate intraoperator variation, the same operator (C.T.) measured all the surfaces and distances in a control subject on different days for a total of 10 times. The mean variation coefficient (ie, SD divided by the mean) was less than 3% for each measurement.
In all patients and control subjects, the operator measured each variable twice consecutively, and the mean of the two measurements was used to calculate the following MR imaging morphometric indexes: basis pontis/PCF, fourth ventricle/PCF, vermis/PCF, cerebellar hemisphere/PCF, medulla/PCF, cervical cord/PCF, and thickness of the middle cerebellar peduncles/PCF.
According to Wullner et al (4), the measurements in individual patients were considered abnormal when they differed by more than 2 SDs from the respective control group values. Three main patterns of atrophy were defined. Patients with CCA demonstrated abnormal values for the cerebellar vermis or hemispheres but had no additional abnormal values, except for the fourth ventricle and middle cerebellar peduncles. Patients with OPCA demonstrated abnormal values for the cerebellar vermis or hemispheres and had at least two abnormal values within the basis pontis, middle cerebellar peduncles, and medulla oblongata, but had no additional abnormal values, except for the fourth ventricle. Patients with SA demonstrated abnormal values for the cervical spinal cord, but had no additional abnormal values, except for the fourth ventricle or medulla.
Possible focal areas of signal intensity changes in the supratentorial brain parenchyma of patients and subjects were assessed visually by another blinded observer (N.V.) who also subjectively graded atrophy of the cerebral hemispheres on a four-point scale (0 = no atrophy, 1 = mild, 2 = moderate, and 3 = severe).
MR spectroscopy.—All MR spectroscopic data were evaluated by one operator (M.T.) who was blind to the group to which the individual belonged and to the MR imaging and clinical data.
With the SAGE/IDL line-fitting program, the areas of the peaks at 2.01, 3.05, 3.25, and 3.56 ppm that corresponded to NAA, Cr, choline (Cho), and myo-inositol (mI) were determined by using a Lorentzian-like shape. We chose not to perform baseline correction because it can affect peak area evaluation (10). The NAA/Cr, Cho/Cr, and mI/Cr ratios were then calculated. In addition, spectra were evaluated for abnormal peaks—notably, lactate at 1.35 ppm.
Statistical evaluation.—A P value of less than .05 was considered to indicate a significant difference. A multiple regression procedure was performed to check for effects of age, sex, disease duration, and disability on the MR imaging morphologic indexes and MR spectroscopic metabolite ratios.
We employed nonparametric one-way analysis of variance by using the Kruskal-Wallis test to evaluate differences in age, morphometric data, and MR spectroscopic data between groups. The differences between each group of patients (ie, OPCA, SA, CCA, and undefined) and control subjects were then evaluated by using the Mann-Whitney test with the Bonferroni adjustment for the multiple comparisons. Correlation of parametric variables, including age, disease duration, and disability; morphologic indexes; and metabolite ratios within each group of ataxic patients were tested by using Spearman rank correlation.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MR Imaging
Morphometry enabled the classification of progressive ataxia in 23 patients. Eight patients with Friedreich ataxia satisfied the criteria for SA. Three patients with autosomal dominant cerebellar ataxia type I and eight patients with idiopathic late-onset cerebellar ataxia with other features exhibited a pattern consistent with OPCA (Fig 1). Two patients with autosomal dominant cerebellar ataxia type III and two patients with idiopathic late-onset pure cerebellar ataxia demonstrated CCA. Two exceptions to the morphometric criteria were noted. In fact, two patients with genetically confirmed Friedreich ataxia showed loss of bulk of the cerebellar vermis. The conditions of seven patients (one with SCA type 1 and six with sporadic ataxia; mean age, 36 years; age range, 15–56 years) were undefined on the basis of the morphometric criteria. Four of the patients with undefined ataxia had one or two morphometric values that exceeded (by more than 2 SDs) the mean values measured in the control subjects but did not fulfill the criteria to be categorized in any of the morphometric groups. In three patients with undefined ataxia, all morphometric values were within 2 SDs of the control values. The morphometric values for the control subjects and the groups of patients with ataxia (both defined and undefined, according to the morphometric criteria) are listed in Table 1.
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Moderate or severe cerebral atrophy was present in one (7%) control subject, two (25%) patients with SA, five (45%) patients with OPCA, two (50%) patients with CCA, and one (14%) patient with undefined ataxia. The differences in frequency of moderate or severe cerebral atrophy between ataxic subgroups and control subjects were significant with the Fisher Exact test only for patients with OPCA (P = .003).
Symmetric hypointensity of the putamen on T2-weighted images was seen in one patient with idiopathic late-onset cerebellar ataxia with other features.
MR Spectroscopy
Figures 2 and 3 show (a) cerebellar and pontine spectra in one patient with idiopathic late-onset cerebellar ataxia with other features and (b) MR imaging findings consistent with OPCA in one control subject.
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Clinical, MR Imaging, and MR Spectroscopic Correlations
No correlation was found between MR imaging and age, disease duration, or disability. A significant (P = .04) correlation between the pontine NAA/Cr ratio and disability score was observed in patients with OPCA.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Harding and Deufel (2) proposed a classification of degenerative ataxia on the basis of clinical and genetic criteria. They distinguished two categories of inherited ataxia: Friedreich ataxia, which is inherited as a recessive trait, and autosomal dominant cerebellar ataxia. The latter was subdivided into type I (ataxia with additional features, such as supranuclear ophthalmoplegia, pseudobulbar palsy, and mild dementia), type II (ataxia with maculopathy), and type III (pure cerebellar syndrome). The sporadic ataxias comprised early-onset cerebellar ataxia with retained tendon reflexes, idiopathic late-onset cerebellar ataxia with other features, and idiopathic late-onset pure cerebellar ataxia.
With the advent of molecular genetic analysis, the diagnosis of Friedreich ataxia can be confirmed (13), and the autosomal dominant cerebellar ataxias have been split into several diseases (termed SCAs), of which eight primary types have been identified (14–17).
Several investigators have studied correlations between the appearance of the brainstem and cerebellum at MR imaging and the clinical genetic profile of patients with degenerative ataxia (3–6,20,21). More recently, MR imaging studies have been focused on subgroups of patients with inherited ataxia that is classified on the basis of molecular genetic analysis (22–25).
The results of the MR imaging–based morphometric evaluations of our patients confirm prior observations. Patients with Friedreich ataxia show an SA pattern (4,21) with additional atrophy of the vermis in advanced phases (5). Patients with autosomal dominant cerebellar ataxia type I and idiopathic late-onset cerebellar ataxia with other features predominantly show an OPCA pattern (4,22,23). Patients with autosomal dominant cerebellar ataxia type III and idiopathic late-onset pure cerebellar ataxia show a CCA pattern (4,20,23,24). Early-onset cerebellar ataxia with retained tendon reflexes is a heterogeneous condition (4,21).
Also, the frequency of both focal white matter lesions and cerebral atrophy has been previously reported (5) as higher in patients with OPCA and CCA than in control subjects.
As expected, degenerative ataxia in seven (23%) of our 30 patients was not classifiable on the basis of morphometry, presumably because of short disease duration or mild disease severity.
Proton MR spectroscopy is increasingly used for the evaluation of degenerative diseases of the central nervous system. In fact, proton MR spectroscopy can noninvasively detect NAA that is a metabolite of unknown function found exclusively in neurons and axons. NAA absolute concentration or the NAA/Cr ratio may serve as a marker of neuroaxonal dysfunction, density, or volume in neurodegenerative processes (26). In particular, the spatial distribution of MR spectroscopic abnormalities can reflect the different burdens of neuroaxonal dysfunction and loss demonstrated in the neuropathologic examination. Examples of such a preferential distribution of the decrease of NAA or NAA/Cr ratio include the motor cortex and the medulla in amyotrophic lateral sclerosis (27,28), the striatum and the frontal cortex in Huntington disease (29,30), and the midfrontal cortex in frontotemporal dementia (31).
In prior proton MR spectroscopic studies of patients with degenerative ataxia, decreased concentrations of NAA or low NAA/Cr ratios were found in the cerebellum, (8–12) and in one study (10), in the pons. In our series, we systematically evaluated (with one small voxel each) the pons and deep cerebellar hemisphere of patients with different types of degenerative ataxia. While other voxel locations such as the cerebellar vermis and medulla were possible, they were excluded to avoid problems (a) with variable degrees of cerebrospinal fluid contamination secondary to cortical cerebellar atrophy and (b) with the difficult and inconstant shimming in the medulla (M. Mascalchi, unpublished data, 2002).
We found a general pattern of proton MR spectroscopic changes in the cerebellum and pons of patients with degenerative ataxia that consisted of a decrease in NAA/Cr ratio with a normal mI/Cr ratio and without detectable lactate. The reduction in the cerebellar and pontine NAA/Cr ratio was significant in patients with OPCA, SA, and CCA. This finding confirms the results of previous MR spectroscopic studies in patients with OPCA (8–12), but it has not been previously reported in patients with SA or CCA who were not included in previous MR spectroscopic studies. While the decrease in NAA/Cr ratio in the cerebellum and pons of patients with SA and CCA casts doubts on the usefulness of MR spectroscopy in distinguishing the different types of degenerative ataxia on the basis of spatial distribution of the NAA/Cr ratio decrease, it can be explained by the distribution of pathologic changes (1), the relatively coarse voxel size, and the occurrence of diaschisis.
The normal mI/Cr ratio we observed in the cerebellum and pons of all groups of patients with degenerative ataxia incidentally provides a convenient internal control, indicating that contribution of different degrees of MR spectroscopic voxel contamination from cerebrospinal fluid related to brainstem or cerebellar atrophy is not a major determinant of NAA/Cr and Cho/Cr ratio changes, since no detectable NAA, Cr, Cho, or mI is present in the cerebrospinal fluid.
Interestingly, we found a significant decrease of Cho/Cr ratio in the pons and cerebellum only in patients with OPCA. This finding is in line with prior studies on patients with SCA type 1 (10) and type 2 (12) and with the significant decrease of Cho observed at MR spectroscopy in a quantitative study of patients with autosomal dominant cerebellar ataxia (8). Further studies are needed to verify if decrease of Cho or Cho/Cr ratio, which might reflect changes in cellular density, total membrane content, and cell signaling activity, is specific to the neurodegenerative process of OPCA, as opposed to other degenerative ataxias in which Cho/Cr ratio or Cho content is not significantly reduced.
It is noteworthy that five of our seven patients with undefined ataxia showed substantial changes at MR spectroscopy. This confirms that, by revealing decrease of the NAA/Cr ratio, proton MR spectroscopy can demonstrate dysfunction of the brainstem or cerebellum when atrophy of the brainstem or cerebellum has not fully developed. Also, MR spectroscopy could be more sensitive than MR imaging–based morphometry in the demonstration of abnormalities in brainstem and cerebellar structures in patients with degenerative ataxia (10). Performing a longitudinal MR imaging study to document the development of atrophy in patients with undefined ataxia who are enrolled in the present investigation could provide an important verification of this assumption and is currently in progress.
The decreased NAA/Cr ratio in the brainstem and cerebellum is not specific to degenerative ataxia. In fact, a decreased NAA/Cr ratio in the pons and medulla is reported in patients with motor neuron disease (27,28,32), and a decreased cerebellar NAA/Cr ratio can be observed in patients with multiple sclerosis (8) and cerebellitis (M. Mascalchi, unpublished data, 2002). However, clinical and MR imaging findings of these conditions are usually different from those of degenerative ataxia (5). Hence, our results suggest that in daily clinical practice, proton MR spectroscopy might serve as an adjunct to MR imaging to support the diagnosis in patients suspected of having degenerative ataxia on the basis of clinical and laboratory findings.
In line with results of prior studies (9,22), we did not observe correlation between disability or disease duration and measurements of brainstem or cerebellar atrophy on MR images. On the contrary, in patients with OPCA (the most numerous ataxia subgroup in our study), the pontine NAA/Cr ratio showed a significant correlation with disability scores. This finding supports the view that MR spectroscopy could be used as a surrogate marker for neuroaxonal dysfunction and loss in patients with degenerative diseases of the central nervous system (26). In particular, it suggests that MR spectroscopy could be used as a secondary outcome measure in addition to clinical evaluation in scientific trials on the assessment of new therapeutic strategies for patients with degenerative ataxia.
We recognize two limitations of our study. The first is the incomplete or missing molecular genetic analysis of some patients. This might implicate an underestimation of patients with genetically determined ataxia who presented with symptoms of sporadic disease. This phenomenon is uncommon, however. In fact, only four of 61 (7%) German patients presenting with symptoms of sporadic ataxia who were screened for SCA type 6 were found to have the expanded allele of this genetically inherited ataxia, which is expected to be the one more frequently mistaken for sporadic disease (24). Moreover, definition of the entire range of genetic abnormalities associated with degenerative ataxia is still incomplete (33), since relatively few screening tests are available. The second limitation is the semiquantitative MR spectroscopic approach we used.
In conclusion, our study results indicate that proton MR spectroscopy can demonstrate neuroaxonal dysfunction in the pons and cerebellum of patients with degenerative ataxia, even when atrophy of the brainstem or cerebellum has not fully developed at MR imaging. This, in conjunction with clinical, laboratory, and MR imaging findings, can be useful in supporting the diagnosis of individual patients. The correlation of the pontine NAA/Cr ratio with functional disability in patients with OPCA suggests that MR spectroscopy can be proposed as a surrogate marker of neuroaxonal damage in patients with degenerative ataxia.
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, N.V.; study concepts, M. Mascalchi; study design, M. Mascalchi, F.L.; literature research, C.A.T., F.S.; clinical studies, R.P., M. Macucci, M.C., F.L.; experimental studies, A.F.; data acquisition, M.T., M.C.; data analysis/interpretation, M. Mascalchi, F.L.; statistical analysis, F.L.; manuscript preparation and definition of intellectual content, M. Mascalchi; manuscript editing, F.L.; manuscript revision/review, F.S.; manuscript final version approval, C.A.T.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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) and patients with SA, OPCA, CCA, and undefined (UN) ataxia on the basis of the MR imaging morphometric evaluation. Error bars and 
indicate the mean and SD in control subjects. The dashed lines identify the cutoff values (2 SDs below the mean of control subjects) across the patient subgroups.